Hodgkin's disease (HD) is unique among human lymphomas in that the tumor cells, known as Hodgkin and Reed Sternberg (H/RS) cells, are exceedingly rare, generally representing 0.1-1% of the total cell population within lymphoma tissue [Drexler, Leukemia and Lymphoma 8:283-313 (1992); Drexler, Leukemia and Lymphoma 9:1-25 (1993); Kadin, Current Opinion in Oncology 6:456:463 (1994); Cossman, et al., Lab. Invest. 78:229-235 (1998)]. As a result, investigation of H/RS cells has been impeded by their low frequency. PCR-based assays of DNA from single H/RS cells have revealed rearranged immunoglobulin genes and somatic mutations, suggesting that H/RS cells are clonal and may be derived from germinal center B cells [Kanzler, et al., J. Exp Med 184:1495-505 (1996); Kÿppers, et al., Annu Rev Immunol 16:471-93 (1998)]. The precise pathogenesis of HD, however, remains to be determined.
Previous observations suggest that the proliferation and survival of HD-derived cells depends on cytokine signaling. It is well established that the unique histology and eosinophilia of HD tissues, and secondary symptoms in the patient such as fever, weight loss, and night sweats, are induced by a pathological pattern of cytokine secretion [Drexler, Leukemia and Lymphoma. 8:283-313 (1992); Drexler, Leukemia and Lymphoma 9:1-25 (1993)]. For example, overexpression of IL-5 in H/RS cells has been previously demonstrated by in situ hybridization, but only in HD patients exhibiting eosinophilia [Samoszuk, et aL, Blood 75:13-16 (1990); Samoszuk, Blood 79:1518-22 (1992)]. To date, no cytokine has been consistently reported as being overexpressed in HD-derived cell lines or in primary H/RS cells.
Evidence for a role for IL-13 in the etiology of HD is indirect. IgE is elevated in HD tissues and serum samples from HD patients [Samoszuk, Blood 79:1518-22 (1992); Thomas, et al., Ann Allergy 37:416-19 (1976)], and IL-13 is known to promote Ig class switching to IgE. IL-13-deficient mice exhibit lower basal levels of serum IgE [McKenzie, et al., Immunity 9:423-432 (1998)]. Furthermore, studies of IL-4 deficient, IL-13 transgenic mice have demonstrated that IL-13 can promote class switching to IgE independently of IL-4 [Emson, et al., J. Exp. Med 188:399-404 (1998)], emphasizing that IL-4 and IL-13 have distinct roles in regulating B cell functions.
IL-13 is a T cell-derived cytokine with immunomodulatory and anti-inflammatory properties [Minty, et al., Nature 362:248-250 (1993)]. The biological effects of IL-13 on B cells, macrophages, and monocytes are very similar to those of IL4, probably because the IL-4 and IL-13 receptors share a common a chain. In B cells, IL-13 promotes proliferation, differentiation, and Ig heavy chain class switching to IgE and IgG4 [Zurawski, et al., Immunology Today 15:19-26 (1994)]. Proliferation results from a signaling pathway in which the engagement of the IL-13 receptor activates JAK1, which in turn activates STAT6 [Lin, et al., Immunity 2:331-339 (1995)].
Other aspects of the HD phenotype may also be attributable to the effects of IL-13. A recent study of IL-13-deficient mice has shown that cultures of type 2 helper T (Th2) cells from these animals produce significantly reduced levels of IL-4, IL-5, and IL-10 compared to the wild type, suggesting an important role for IL-13 as a regulator of Th2 cell commitment [McKenzie, et al., Immunity 9:423-432 (1998)]. If IL-13 is also important for promoting the differentiation of Th2 cells in humans, it could explain why H/RS cells (which secrete IL-13) are surrounded by Th2 cells in HD biopsies. In addition, because fibroblasts express the IL-13 receptor and can be activated by IL-13 [Doucet, et al., J. Clin Invest 101:2129-2139 (1998)], the secretion of IL-13 by H/RS cells may underlie the pathogenesis of the fibrosis observed in nodular sclerosis HD.
Thus, there exists a need in the art to identify specific growth factors that participate in the pathogenesis of HD. In particular, identification of cytokines that stimulate H/RS cell proliferation will facilitate development of methods for therapeutic invention, by way of (i) modulating expression of the cytokine(s), (ii) modulating biological activity of the cytokine(s), and (iii) modulating both expression and biological activity.